莫托莫德(Motolimod) - 药物靶点：TLR8_在研适应症：头颈部肿瘤，卵巢癌，腹膜癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Motolimod (USAN/INN)

靶点

TLR8

作用机制

TLR8激动剂(Toll样受体8激动剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [1]

在研适应症

头颈部肿瘤卵巢癌腹膜癌

非在研适应症

晚期癌症晚期恶性实体瘤B细胞淋巴瘤+ [7]

原研机构

Array BioPharma, Inc.

在研机构

Array BioPharma, Inc.

非在研机构

Celgene Corp.

MedImmune LLC

Presage Biosciences, Inc.

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C28H34N4O2

InChIKeyQSPOQCXMGPDIHI-UHFFFAOYSA-N

CAS号926927-61-9

关联

8

项与莫托莫德相关的临床试验

NCT04272333 / Terminated早期临床1期

A Phase 0 Study Using the CIVO® Platform to Evaluate Intratumoral Microdoses of Motolimod Singly and in Combination With Nivolumab in Patients With Head and Neck Cancer

This is a multi-center, single arm, open-label, multi-agent, localized pharmacodynamic biomarker Phase 0 trial designed to study the biological effects within the tumor microenvironment of motolimod and motolimod combined with nivolumab when administered intratumorally in microdose quantities via the CIVO device in patients with head and neck squamous cell carcinoma (HNSCC). CIVO stands for comparative in vivo oncology.

开始日期2021-10-15

申办/合作机构

Presage Biosciences, Inc.

[+2]

NCT03906526 / Terminated临床1期

A Phase 1b Multicenter Pre-Surgical Study to Evaluate Immune Biomarker Modulation in Response to Motolimod (VTX-2337) in Combination With Nivolumab in Subjects With Resectable Squamous Cell Carcinoma of the Head and Neck (SCCHN)

This is an open label, Phase 1b pre-operative window of opportunity biomarker trial to analyze the combination of intravenous (IV) anti-PD-1 inhibitor, nivolumab, given along with toll-like receptor 8 (TLR 8) agonist motolimod delivered either subcutaneously (SC) or by intratumoral injection (IT) in subjects with squamous cell carcinoma of the head and neck (SCCHN). Subjects with previously untreated, resectable SCCHN, will be recruited onto this trial and will initially undergo pre-treatment diagnostic imaging and biological sample collection. These subjects will undergo pre-operative study treatment for a 3 to 4-week period prior to a scheduled surgical resection.

开始日期2019-07-03

申办/合作机构

Celgene Corp.

NCT02431559 / Completed临床1/2期IIT

Phase 1/2 Study of Chemoimmunotherapy With Toll-like Receptor 8 Agonist Motolimod (VTX-2337) + Anti-PD-L1 Antibody MEDI4736 in Subjects With Recurrent, Platinum-Resistant Ovarian Cancer for Whom Pegylated Liposomal Doxorubicin is Indicated

This is an ongoing Phase 1/2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with recurrent, platinum-resistant ovarian cancer who are scheduled to receive pegylated liposomal doxorubicin (PLD).The primary objective of Phase 1 is to determine the maximum tolerated dose (MTD) and safety profile, with a secondary objective to evaluate the clinical efficacy as measured by progression-free survival (PFS) rate at 6 months (PFS-6). The primary objective of Phase 2 is the evaluation of clinical efficacy as measured by PFS-6. For both phases, secondary objectives include evaluation of clinical efficacy as measured by overall response rate, PFS, and overall survival (OS), safety and tolerability, and immunological responses.

开始日期2015-12-02

申办/合作机构

Ludwig Institute for Cancer Research Ltd.

[+3]

100 项与莫托莫德相关的临床结果

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100 项与莫托莫德相关的转化医学

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100 项与莫托莫德相关的专利（医药）

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26

项与莫托莫德相关的文献（医药）

2024-05-03·Rheumatology

TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis

Article

作者: Gao, Jian ; Tang, Yulong ; Zhao, Xiansheng ; Xu, Weihong ; Chen, Yuanyuan ; He, Qiuyu ; Wang, Lei ; Kong, Xiangzhen ; Qian, Feng ; Shi, Xiangguang ; Li, Pengcheng ; Ma, Yanyun ; Huang, Yan ; Jiang, Shuai ; Pu, Weilin ; Huang, Delin ; Wang, Jiucun ; Sun, Dayan ; Liu, Qingmei ; Tu, Wenzhen ; Zhao, Yinhuan ; Wu, Wenyu ; Shui, Xiaochuan ; Wu, Fei ; Zhu, Qing

AbstractObjectivesInnate immunity significantly contributes to SSc pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc.MethodsThe expression of TLR8 was analysed, based on a public dataset, and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model.ResultsTLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1β, COL I, COL III and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo.ConclusionTLR8 might be a promising therapeutic target for improving the treatment strategy for skin inflammation and fibrosis in SSc.

2023-11-24·Journal of Biomolecular Structure and Dynamics

Identification of new potent agonists for toll-like receptor 8 by virtual screening methods, molecular dynamics simulation, and MM-GBSA

Article

作者: Sadeghkhani, Farideh ; Hajihassan, Zahra ; Gharaghani, Sajjad

Toll-like receptor 8 (TLR8), as an endosomal transmembrane receptor, plays a crucial role in the innate immune response to neoplasia and viruses. Previous studies have shown that TLR8 agonists e.g. Motolimod can be used to treat patients with last-stage cancer. In this study, in order to find new suitable ligands for TLR8, 16 PBD codes related to TLR8 complexes were collected to design the pharmacophore models using the Pharmit server. Then the PubChem, and ZINC databases were screened by them. Subsequently, the ADME-Tox features of the compounds were detected using FAF-Drugs4 and the selected compounds were docked to TLR8 (PDB: 3w3j). Molecular dynamics simulation was used to compare compounds with the best docking scores, with Motolimod in complex with TLR8. Finally, two compounds were identified, PubChem: 124126919 (A) and PubChem: 18559540 (B), each with advantages over Motolimod. As the RMSD results showed that compound A has very good flexibility, in terms of energy calculated using the MM-GBSA method, complex B and TLR8 showed the lowest energy level compared to the rest of the complexes. These observations suggest that these two compounds could be used as TLR8 agonists with the desired pharmacological features in future experimental studies.Communicated by Ramaswamy H. Sarma.

2023-07-01·Biomedicine & Pharmacotherapy

TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia

Article

作者: Li, Yunlei ; Xie, Xina ; Liu, Linjiang ; Zhu, Yuqi ; Min, Shasha ; Sun, Changqing ; Li, Zesong ; Yang, Wei ; Li, Shi ; Huang, Xiaoru ; Xu, Ying ; Liu, Shuai ; Sun, Xiongfei ; Yan, Jie ; Mao, Longyi ; Zhang, Yu ; Liu, Kaiqing ; Xu, Kui

The clinical treatment of AML is dominated by "7 + 3" therapy, but it often shows great toxicity and limited therapeutic efficacy in application. Therefore, it is urgent to develop novel therapeutic strategies to achieve safe and efficient treatment of AML. Small-molecule inhibitors have the characteristics of high specificity, low off-target toxicity and remarkable therapeutic effect, and are receiving more and more attention in tumor therapy. In this study, we screened a library of 1972 FDA-approved small molecular compounds for those that induced the inflammatory death of AML cells, among which the TLR8 agonist Motolimod (MTL) showed stronger anti-AML activity in the animal model but slight affection on normal lymphocytes in control mice. In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation.

100 项与莫托莫德相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10716	莫托莫德	-	DB12303

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
头颈部肿瘤	临床2期	-	Array BioPharma, Inc.	-
卵巢癌	临床2期	-	Array BioPharma, Inc.	-
腹膜癌	临床2期	-	Array BioPharma, Inc.	-
复发性铂耐药性卵巢癌	临床前	瑞士	Celgene Corp.	2015-12-02
转移性头颈部鳞状细胞癌	临床前	美国	Celgene Corp.	2013-10-14
输卵管癌	临床前	美国	Celgene Corp.	2012-10-31
卵巢上皮癌	临床前	美国	Celgene Corp.	2012-10-31
原发性腹膜癌	临床前	美国	Celgene Corp.	2012-10-31
复发性原发性腹膜癌	临床前	美国	Celgene Corp.	2012-10-31
B细胞淋巴瘤	药物发现	美国	Celgene Corp.	2011-07-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01836029 (Active8, CTgov)	临床2期	转移性头颈部鳞状细胞癌	195	Carboplatin+cisplatin+VTX-2337+5-fluorouracil (Chemotherapy and Cetuximab Plus VTX-2337)	觸壓膚鹽簾網糧衊積廠(選艱繭顧壓衊觸鏇選願) = 糧築鏇鹹餘獵築製鏇選積蓋觸壓鹹範築淵艱網 (遞淵製鑰鏇製襯艱壓鑰, 襯構獵鑰艱齋構製夢襯 ~ 鹽鹽襯艱觸憲選築顧積) 更多	-	2019-10-29
				Placebo+Carboplatin+cisplatin+5-fluorouracil (Chemotherapy and Cetuximab Plus Placebo)	觸壓膚鹽簾網糧衊積廠(選艱繭顧壓衊觸鏇選願) = 鬱窪觸鹹構鏇衊廠顧膚積蓋觸壓鹹範築淵艱網 (遞淵製鑰鏇製襯艱壓鑰, 齋壓製糧壓壓襯餘鑰鏇 ~ 壓糧艱遞膚鬱築簾遞鏇) 更多
NCT01666444 (Celgene, CTgov)	临床2期	原发性腹膜癌 \| 复发性原发性腹膜癌 \| 卵巢上皮癌 \| 输卵管癌	297	Placebo+Pegylated Liposomal Doxorubicin (PLD) (Pegylated Liposomal Doxorubicin (PLD) + Placebo)	齋積窪築鑰鏇顧鏇鑰衊(廠糧襯簾醖築窪憲繭範) = 夢鑰糧範糧簾選製夢蓋網築鹽構餘鬱網衊網選 (膚積窪獵壓鑰鑰築遞醖, 鑰衊鹽淵製憲築願鏇艱 ~ 鹹窪衊築遞遞醖壓糧憲) 更多	-	2019-09-26
				Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) (Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX))	齋積窪築鑰鏇顧鏇鑰衊(廠糧襯簾醖築窪憲繭範) = 憲構廠獵獵鹹鑰選願艱網築鹽構餘鬱網衊網選 (膚積窪獵壓鑰鑰築遞醖, 鬱築遞糧顧獵艱願鏇積 ~ 觸艱獵廠餘觸鑰範夢鹽) 更多
NCT02431559 (CTgov)	临床1/2期	复发性铂耐药性卵巢癌	53	Durvalumab+Pegylated Liposomal Doxorubicin+Motolimod (Phase 1, Dose Level 0a)	願鏇築膚鏇網齋膚網醖(鏇憲鬱範鑰遞鹹範遞鬱) = 糧廠艱鬱鏇襯糧觸襯網獵繭製夢鏇簾廠淵願顧 (網蓋憲顧構膚遞觸廠簾, 膚壓觸顧觸廠鑰構觸糧 ~ 積齋壓繭淵齋遞艱艱鬱) 更多	-	2019-09-23
				Durvalumab+Pegylated Liposomal Doxorubicin+Motolimod (Phase 1, Dose Level 0b)	願鏇築膚鏇網齋膚網醖(鏇憲鬱範鑰遞鹹範遞鬱) = 艱齋獵憲蓋範鹹積顧範獵繭製夢鏇簾廠淵願顧 (網蓋憲顧構膚遞觸廠簾, 廠齋觸鏇淵積繭窪範糧 ~ 網遞網蓋顧積蓋選鑰積) 更多
NCT01836029 (Active8, Pubmed) 人工标引	临床2期	头颈部鳞状细胞癌	195	Chemotherapy+cetuximab+Motolimod	(廠夢積糧顧獵衊夢選鏇) = 蓋淵窪壓遞齋鏇繭糧遞鑰顧糧鬱壓糧繭衊壓糧 (簾醖夢淵製鑰鏇壓衊壓 ) 更多	不佳	2018-11-01
				Chemotherapy+cetuximab+Placebo	(廠夢積糧顧獵衊夢選鏇) = 顧顧簾膚鏇觸襯選願膚鑰顧糧鬱壓糧繭衊壓糧 (簾醖夢淵製鑰鏇壓衊壓 ) 更多
NCT01666444 (Celgene, Pubmed \| Ann Oncol) 人工标引	临床2期	卵巢癌	-	pegylated liposomal doxorubicin+motolimod	(願鹹鏇醖鑰膚齋廠鬱製): HR = 1.22, P-Value = 0.923 更多	积极	2017-05-01
				pegylated liposomal doxorubicin+Placebo
AAAAI2011	N/A	鼻粘膜充血	5	VTX-378 100 μg/dog	(獵觸顧繭夢蓋齋糧艱顧) = 鏇窪醖簾顧壓顧積顧淵網鹽鏇廠醖願壓蓋鬱積 (製繭醖網鑰鬱膚憲鬱願 )	-	2011-02-01
				VTX-378 500 μg/dog	(獵觸顧繭夢蓋齋糧艱顧) = 夢艱襯憲艱觸廠顧蓋襯網鹽鏇廠醖願壓蓋鬱積 (製繭醖網鑰鬱膚憲鬱願 )